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The purpose of this research study is to learn about the medical effects, safety, and how the Walnut Oral Immunotherapy (OIT) treatment affects your body (immune system). This type of immunotherapy involves giving increasing doses of walnut allergen to gradually build up a person's tolerance to walnut and at least one other tree nut. The goal of the study is to determine whether participants can tolerate (eat) walnuts and at least one other tree nut in their diet after stopping the study therapy.

The primary clinical efficacy outcome of the study will be the change from baseline OFC in cumulative dose reached at the desensitization OFC to the test tree nut.

Secondary Outcome Measures:

The percentage of subjects who reach a cumulative dose of 5000 mg and 2000 mg at the desensitization OFC to walnut and to the test tree nut (desensitization OFC is at ~38 weeks) [ Time Frame: 38 weeks ]

1.The percentage of subjects who reach a cumulative dose of 5000 mg and 2000 mg at the desensitization OFC to walnut and to the test tree nut (desensitization OFC is at ~38 weeks)

The percentage of subjects who reach a cumulative dose of 5000 mg and 2000 mg at the desensitization OFC to walnut and to the test tree nut (desensitization OFC is at ~38 weeks) [ Time Frame: 38 weeks ]

2.The percentage of subjects that demonstrate clinical tolerance at end of study to walnut and to the test tree nut.

The percentage of subjects who reach a cumulative dose of 5000 mg and 2000 mg at the desensitization OFC to walnut and to the test tree nut (desensitization OFC is at ~38 weeks) [ Time Frame: 38 weeks ]

3.The change in immune parameters over time including humoral responses, basophil/effector cell responses, and cytokine responses to tree nuts in cultured cells over time.

The percentage of subjects who reach a cumulative dose of 5000 mg and 2000 mg at the desensitization OFC to walnut and to the test tree nut (desensitization OFC is at ~38 weeks) [ Time Frame: 38 weeks ]

Subjects will be randomized in a 2:1 ratio into either an active treatment group (final dose 1500 mg walnut protein, n=20) or a placebo group (n=10). Subjects will undergo a one-day desensitization protocol designed to enable the subject to tolerate 6 mg of walnut protein or placebo (initial day escalation phase). After the initial escalation day achieving at least 1.5 mg and up to 6 mg of walnut protein or placebo, dosing build-up will occur every two weeks through dose 24 at 34 weeks. A maintenance dose will be given for 4 weeks followed by a 5 gram protein OFC to walnut and a 5 gram protein OFC to a second tree nut (at ~38 weeks), after which the study will be unblinded.

Drug: walnut powder

escalating doses of walnut powder

Placebo Comparator: placebo arm

Subjects will be randomized in a 2:1 ratio into either an active treatment group (final dose 1500 mg walnut protein, n=20) or a placebo group (n=10). Subjects will undergo a one-day desensitization protocol designed to enable the subject to tolerate 6 mg of walnut protein or placebo (initial day escalation phase). After the initial escalation day achieving at least 1.5 mg and up to 6 mg of walnut protein or placebo, dosing build-up will occur every two weeks through dose 24 at 34 weeks. A maintenance dose will be given for 4 weeks followed by a 5 gram protein OFC to walnut and a 5 gram protein OFC to a second tree nut (at ~38 weeks), after which the study will be unblinded. Placebo subjects that fail the OFC will be crossed over to active treatment and escalated as described to the 1500 mg target dose.

Drug: walnut powder

Subjects will be randomized in a 2:1 ratio into either an active treatment group (final dose 1500 mg walnut protein, n=20) or a placebo group (n=10). Subjects will undergo a one-day desensitization protocol designed to enable the subject to tolerate 6 mg of walnut protein or placebo (initial day escalation phase). After the initial escalation day achieving at least 1.5 mg and up to 6 mg of walnut protein or placebo, dosing build-up will occur every two weeks through dose 24 at 34 weeks. A maintenance dose will be given for 4 weeks followed by a 5 gram protein OFC to walnut and a 5 gram protein OFC to a second tree nut (at ~38 weeks), after which the study will be unblinded. Placebo subjects that fail the OFC will be crossed over to active treatment and escalated as described to the 1500 mg target dose.

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

Ages Eligible for Study:

6 Years to 21 Years (Child, Adult)

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

No

Criteria

Inclusion Criteria:

Age 6 to 21 years, either sex, any race, any ethnicity with a convincing clinical history of walnut or another tree nut allergy and either a positive prick skin test (>3mm) or serologic evidence of allergic sensitization (defined as specific IgE>0.35 kU/L) to walnut and at least one other tree.

A positive <2000 mg protein oral food challenge at enrollment to walnut and to one other tree nut.

Written informed consent from participant and/or parent/guardian, including assent where indicated.

All females of child-bearing age must be using appropriate birth control or practicing abstinence.

Exclusion Criteria:

History of severe anaphylaxis to walnut or other tree nuts, defined as symptoms associated with hypoxia, hypotension or neurologic compromise (cyanosis or SpO2<92% at any stage, hypotension, confusion, collapse, loss of consciousness; or incontinence).

Known allergy to oat

Chronic disease (other than asthma, atopic dermatitis, rhinitis) requiring therapy or other respiratory or medical conditions deemed by the investigator to put subject at increased risk of anaphylaxis or poor outcomes from receiving OIT or undergoing food challenge.

Poor control or persistent activation of atopic dermatitis

Active eosinophilic or other inflammatory (e.g., celiac) gastrointestinal disease in the past 2 years.

Participation in any interventional study for food allergy in the past 6 months

Participant is on "build-up phase" of immunotherapy (i.e., has not reached maintenance dosing).

Severe asthma (2007 NHLBI Criteria Steps 5 or 6, see Appendix 2)

Mild or moderate (2007 NHLBI Criteria Steps 1-4) asthma with any of the following criteria met:

FEV1 < 80% of predicted, or FEV1/FVC < 75%, with or without controller medications or

History of daily oral steroid dosing for > 1 month during the past year or

Burst of oral, IM, or IV steroids for >3 days in the past 6 months for asthma control or

> 1 burst of oral, IM or IV steroids in the past year for asthma control or

> 1 hospitalization in the past year for asthma or

> 1 ER visit in the past 6 months for asthma

Inability to discontinue antihistamines for initial day escalation, skin testing or OFC

Use of omalizumab or other non-traditional forms of allergen immunotherapy (e.g., oral or sublingual) or immunomodulator therapy (not including corticosteroids) or biologic therapy within the past year